review Annals of Oncology 19: 433–442, 2008

doi:10.1093/annonc/mdm350
Published online 24 October 2007

Thrombotic and infectious complications of central

venous catheters in patients with hematological
malignancies
R. S. Boersma1*, K.-S. G. Jie1, A. Verbon2, E. C. M. van Pampus3 & H. C. Schouten3
1
Atrium Medical Centre Heerlen, Department of Internal Medicine, Heerlen; 2University Hospital Maastricht, Department of Medical Microbiology and Department of
Internal Medicine, Division of General Internal Medicine, Section Infectious Diseases; 3University Hospital Maastricht, Department of Internal Medicine, Division of
Haematology, Maastricht, The Netherlands

Received 22 February 2007; revised 6 June 2007; accepted 8 June 2007

Central venous catheters (CVCs) have considerably improved the management of patients with hematological
malignancies, by facilitating chemotherapy, supportive therapy and blood sampling. Complications of insertion
of CVCs include mechanical (arterial puncture, pneumothorax), thrombotic and infectious complications.

review
CVC-related thrombosis and infections are frequently occurring complications and may cause significant
morbidity in patients with hematological malignancies. CVC-related thrombosis and infections are related and
can therefore not be seen as separate entities. The incidence of symptomatic CVC-related thrombosis had
been reported to vary between 1.2 and 13.0% of patients with hematological malignancy. The incidence of
CVC-related bloodstream infections varies between 0.0 and 20.8%. There is need for a specific approach
regarding diagnosis and treatment of CVC-related thrombosis and infection with specific attention to the
preservation of the catheter. Since data on CVC-related infections and thrombosis in hematological patients
have been obtained mainly from retrospective studies of small sample size, prospective, randomized studies
of prophylactic measures concerning CVC-related thrombosis and infection are warranted.
Key words: central venous catheter-related infections, central venous catheter-related thrombosis, hematological
malignancies

introduction perhaps contraindicate the use of antithrombotic prophylaxis.

Central venous catheters (CVCs) are frequently used in
patients with a hematological malignancy in order to
administer chemotherapy, stem cell infusions, blood products,
medication, parenteral hyperalimentation as well as for blood
sampling.
Reported complications consist of mechanical complications
during or directly after the insertion (arterial puncture,
hematoma and pneumothorax) and long-term complications
such as infection and thrombosis [1]. CVC-related thrombosis
and infections result in patient morbidity, significant increases
in the length of hospitalization and medical care costs [2, 3].
Many studies have addressed the incidence and associated
risk factors of CVC-related infections and thrombosis in
patients with solid tumors, but only few data are available on
hematological patients. These patients may differ from patients
with solid tumors with respect to more severe and prolonged
thrombocytopenia and leucopenia [4, 5]. Thrombocytopenia is
associated with a trend for reduced risk of thrombotic
complications [4], but might increase the risk of bleeding and
*Correspondence to: Dr R. S. Boersma, University Hospital Maastricht, Department of
Internal Medicine, Postbus 5800, 6202 AZ Maastricht, The Netherlands.
Tel: +31-43-3877005; Fax: +31-43-3875006; E-mail: rinskeboersma@hotmail.com
Patients with severe and sustained neutropenia are at high risk
of infectious complications.
Since CVC-related thrombosis and CVC-related infections
cannot be seen as separate entities, this review focuses on the
epidemiology, pathogenesis, diagnosis, prevention and
treatment of both CVC-related thrombosis and CVC-related
infections in patients with a hematological malignancy.
CVC-related thrombosis
CVC-related thrombosis may be asymptomatic and
demonstrated by screening diagnostic imaging or present
with symptoms. An asymptomatic CVC-related thrombosis is
found in 1.5–34.1% of patients with a hematological
malignancy (see Table 1). About two-thirds of all thromboses
are clinically silent. The presence of asymptomatic thrombosis
increases the risk of developing symptomatic thrombosis
7-fold compared with negative Doppler ultrasound findings
(RR 6.8; 95% CI 2.3–20.2) [6].
Symptomatic CVC-related thrombosis is defined as
thrombosis objectified by diagnostic imaging upon overt
symptoms and signs and is found in 1.2–13.0% of patients with
a hematological malignancy (see Table 1).

ª The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
review Annals of Oncology

Table 1. Incidence of CVC-related thrombosis in hematological patients

Author Year Study design No. CVCs CVC-related (A)Symptomatic CVC care
thrombosis, n (%)
Boraks et al. 1998 Retrospective 115 15 (13.0) Symptomatic Heparin flush twice weekly
Prospective 108 5 (4.6) Symptomatic Heparin flush and warfarin 1 mg/day
Ratcliffe et al. 1999 Prospective 23 2 (8.7) Symptomatic Daily heparin–saline flushes
Nouwen et al. 1999 Prospective 48 7 (14.6) (A)Symptomatic Not mentioned
Lagro et al. 2000 Retrospective 163 10 (6.1) Symptomatic Dailly heparin–saline flushes/no
prophylaxis
125 10 (8.0) Symptomatic 7 days nadroparin s.c.
102 7 (6.9) Symptomatic 10 days nadroparin s.c.
Fijnheer et al. 2002 Prospective 94 9 (9.6) Symptomatic Daily heparin-saline flushes
183 23 (12.6) Symptomatic 10 days of LMWH s.c/4 weeks of heparin
Harter et al. 2002 Prospective 233 4 (1.5) (A)Symptomatic 10,000 IE heparin i.v./day
Male et al. 2003 Prospective 85 children 29 (34.1) (A)Symptomatic Continuous UFH or flushes
Lordick et al. 2003 Prospective 43 13 (30.2) (A)Symptomatic Continuous UFH/LMWH s.c/low-dose
heparin
Cortelezzi et al. 2003 Retrospective 137 14 (10.2) Symptomatic Weekly heparin flush and LMWH or
UFH or none
Van Rooden et al. 2005 Prospective 105 13 (12.4) Symptomatic Daily urokinase in lumina of the CVC
Abdelkefi et al. 2005 Prospective 102 10 (9.8) (A)Symptomatic Saline infusion
102 2 (2.0) (A)Symptomatic Continuous infusion of UFH
Cortelezzi et al. 2005 Prospective 458 35 (7.6) Symptomatic Not mentioned
14.2% antithrombotic prophylaxis
Magagnoli et al. 2006 Retrospective 254 3 (1.2) Symptomatic 1 mg of warfarin daily

(A)Symptomatic: symptomatic and/or asymptomatic.

The observed incidence of CVC-related thrombosis varies
considerably among the different studies, reflecting
differences in type of CVCs, study design and duration,
study population and sensitivity of the examination
procedures.
The incidence of CVC-related thrombosis seems to be higher
in older studies compared with more recent studies which may
be explained by improvements in CVC insertion technique
and/or improvements in the biocompatibility of the CVCs.
Currently used CVCs are composed of silicon or polyurethane
and are less often associated with local thrombosis than the
CVCs made of polyethylene [7].
Symptoms of CVC-related thrombosis vary widely and
consist of swelling or pain of arm/neck/head, headache,
numbness of the extremity, erythema of the extremity,
phlegmasia, venous distension and jaw pain. The median
number of days between line insertion and CVC-related
thrombosis is 16–23 [4, 6, 8–10].
CVC-related thrombosis may have serious complications.
The catheter is located deep in the mediastinum and
thrombosis may be clinically silent until late in its course.
Pulmonary embolism occurs in 15–25% of patients with
a symptomatic CVC-related thrombosis [11, 12], postphlebitic
syndrome arises in 14.8% of patients with an upper-extremity
deep vein thrombosis [13] and there is an increased risk of
CVC-related infection [14–16].
Asymptomatic thrombosis may be clinically important. A
strong association between asymptomatic CVC-related
thrombosis and catheter complications like occlusion of the
CVC and CVC-related infection has been reported [14, 15].
pathogenesis and risk factors for CVC-related
thrombosis
The pathogenesis of CVC-related thrombosis is multifactorial.
Vessel damage, a major component of Virchow’s triad, plays an
important role. Vessel damage can be caused by a variety of
factors such as mechanical injury of the venous endothelium by
the catheter during insertion, the number of vein punctures
[17] and irritation of the vessel wall by chemotherapeutic
agents [18, 19].
After the insertion of a CVC, a fibrin sheath can form around
the CVC. The development of a CVC-related sleeve has been
reported to occur in up to 47% of patients with CVCs [20, 21].
The catheter sleeve is an adherent coating of fibrin and collagen
that may envelope the CVC. This fibrin sleeve is in itself
a benign complication, but can cause catheter malfunction,
facilitates the development of infection and may lead to mural
thrombosis.
Mural thrombosis can cause subtotal stenosis or occlusion of
the venous lumen and may lead to clinically manifest
thrombosis or associated complications. Mural thrombosis is
often found near the entry site of the CVC into the vessel or at
the junction of the large veins.
There are several risk factors for CVC-related thrombosis,
such as CVC biocompatibility, catheter tip position, side of
insertion, puncture site of insertion, thrombophilic
abnormalities and CVC-related infections.
The position of the catheter tip in the vascular system is an
important risk factor for the development of CVC-related
thrombosis. The incidence of CVC-related thrombosis is higher

434 | Boersma et al. Volume 19 | No. 3 | March 2008

Annals of Oncology
in patients in whom the catheter tip is placed in the innominate
vein or proximal superior vena cava as compared with the distal
superior vena cava/right atrial junction [22, 23]. Tesselaar et al.
[24] showed a 2.6-fold higher risk when the catheter was
located in the superior vena cava compared with the right
atrium. The risk of CVC-related thrombosis was 8-fold higher
for arm ports than for chest ports.
The side of insertion and puncture site of insertion are other
important risk factors. Tesselaar et al. [24] showed left-sided
placement to be associated with a 3.5-fold increased risk for
CVC-related thrombosis compared with right-sided placement.
In children with acute lymphoblastic leukemia, left-sided CVCs
were also associated with an increased incidence of CVC-related
thrombosis. Patients with a CVC in the subclavian vein had
a 44% (22 of 50) incidence of CVC-related thrombosis
compared with a 20% (7 of 35) incidence in patients with
a jugular vein CVC (P = 0.025) [25]. A possible explanation for
all this lies in the anatomy of the upper body venous system.
In comparison with the right side, the left brachiocephalic
vein is longer and has a more horizontal course, leading to
a sharper angle into the superior vena cava. Compared with
jugular CVCs, subclavian CVCs follow an even sharper curve
into the central venous system, resulting in wall adherence.
The CVC enters where the vein passes between the clavicle and
the first rib, which may cause vein compression and kinking
of the CVC [25].
Whether the factor V Leiden mutation should be regarded as
an increased risk factor is still not established. In one study
patients with the factor V Leiden mutation had a 7.7-fold
increased risk of CVC-related thrombosis after an allogeneic
bone marrow transplantation. [26]. Van Rooden et al. [27] also
found an increased relative risk of 2.6 (CI 95% 1.9–3.8) for
CVC-related thrombosis in the factor V Leiden mutation
group. Two other studies, however, showed no significant
contribution of factor V Leiden on the development of CVC-
related thrombosis [24, 28].
CVC-related infections contribute to the pathogenesis of
thromboembolic complications [16, 29, 30]. Van Rooden et al.
reported in a prospective study in a population of
hematological patients an increased risk of CVC-related
thrombosis in patients with a CVC-related infection
compared with those without infection (relative risk 17.6;
95% CI 4.1–74.1) [29].
diagnosis of CVC-related thrombosis
Contrast venography is considered the gold standard in
detecting upper limb-venous thrombosis (UL-VT). Routine
application, however, is limited due to its invasive nature and
the use of a contrast medium. Compression ultrasound (CUS)
with Doppler and color imaging is more easily applicable for
the detection of thrombosis and is therefore more widely used.
In a systematic review of studies on the diagnosis of
suspected UL-VT a sensitivity of CUS ranging from 56% to
100% and a specificity ranging from 94% to 100% has been
reported [31]. CUS in experienced hands can be regarded as
a sufficient diagnostic tool in patients in whom a CVC-related
thrombosis is suspected clinically. If the CUS is negative in
a patient with a high clinical suspicion of CVC-related
thrombosis, a contrast venography should be performed.
Volume 19 | No. 3 | March 2008
review
is antithrombotic prophylaxis indicated?
It is still a matter of debate whether antithrombotic prophylaxis
in hematological patients with a CVC is indicated and if so,
which type of drug is recommended. It is estimated that
currently <10% of hemato-oncological patients with CVCs
receive any kind of systematic prophylaxis [32, 33]. Many
physicians are reluctant to prescribe anticoagulant prophylaxis
for the prevention of CVC-related thrombosis because of a low
expected incidence of clinically manifest thrombosis and a
presumed high risk of bleeding in these often thrombocytopenic
patients [32, 33]. The use of antithrombotic prophylaxis has
been evaluated mainly in patients with solid tumors; only
limited evidence-based data are available in patients with
hematological malignancies. Only a few prospective, well-
conducted, randomized studies of prophylactic strategies in
hematological patients have been performed.
In a well-conducted, randomized double blind trial, Couban
et al. [34] found that the administration of warfarin 1 mg daily
did not reduce the incidence of symptomatic CVC-related
thrombosis in a patient population with mostly hematological
malignancies. Major limitations of their study were the
unexpectedly low incidence of thrombosis (only 11
symptomatic CVC-related thromboses in 255 patients) and the
timing of starting warfarin (study drug was always
administered after CVC insertion and may have been started up
to 72 h later).
Another prospective randomized controlled trial has
been published comparing continuous intravenous
unfractionated heparin (UFH) with normal saline solution as
a continuous infusion in patients with a hematological
malignancy. CVC-related thrombosis occurred in 1.5% of the
CVCs inserted in patients of the heparin group, and in 12.6%
of the control group (P = 0.03). Two patients in the heparin
group and three patients in the control group experienced
severe bleeding (P = 0.18) [35]. Dillon et al. [36] showed in
a prospective, randomized study which included patients
£21 years of age with an implantable port or tunneled
catheter that flushing the CVC with urokinase every 2 weeks
resulted in fewer occlusive events than flushing with heparin
(23% versus 31%; P = 0.02). A number of non-randomized
studies of pharmacologic prophylaxis in hematological patients
have been carried out.
In an attempt to reduce CVC-related thrombosis 108
consecutive patients with hematological malignancies were
started on minidose warfarin (1 mg warfarin daily) at the time
of line insertion. Five (5%) of the 108 patients developed
a CVC-related thrombosis. A major drawback in this study was
the use of a historic control group of 115 consecutive patients
who had not received warfarin. In this control group 15
patients (13%) developed a CVC-related thrombosis. The
difference between the groups was statistically significant
(P = 0.03) [10].
In a retrospective study with minidose warfarin three
CVC-related thromboses were observed in 254 CVCs. Four
episodes of bleeding were seen. It was therefore concluded that
minidose warfarin is effective and safe to use for preventing
CVC-related thrombosis. Unfortunately also in this study
an adequate control group was not included [37].
doi:10.1093/annonc/mdm350 | 435
review
Lagro et al. [9] found no effect using prophylactic
nadroparin on the incidence of CVC-related thrombosis in 382
patients receiving a stem cell transplantation. Their study
however, has a retrospective design and the patients only
received nadroparin for the first 6–10 days after insertion of the
CVC. Since CVC-related thrombosis is observed at a median of
16–23 days after insertion of the CVC the time course of
nadroparin administration may have been too short.
Due to the lack of well-designed, prospective studies, the
optimal antithrombotic prophylaxis in patients with
hematological malignancies remains a matter of debate. Further
prospective, well-conducted, randomized studies of
prophylactic strategies are clearly warranted.
treatment of CVC-related thrombosis
The aims of treatment of CVC-related thrombosis are to reduce
the mortality and morbidity from the acute event and to reduce
late complications.
The management of patients who develop a CVC-related
thrombosis is not standardized. Treatment strategies consist of
thrombolytic therapy, initiation of systemic anticoagulation,
removal of the catheter or both.
In non-hematological patients with a CVC-related
thrombosis the preferred treatment is the combination of a low
molecular weight heparin (LMWH) followed by oral
anticoagulation for at least 3–6 months [38, 39]. No
prospective, randomized studies have been published on this
subject.
The management of thrombosis in hematological and often
thrombocytopenic patients is difficult because LMWH and
oral anticoagulant are relatively contraindicated because of
the high risk of major bleeding.
There is only limited information on the treatment of CVC-
related thrombosis in hematological patients. No randomized
trials have been published on this subject in the literature.
In a retrospective study the treatment and outcome of 112
cancer patients with a CVC-related thrombosis was reported.
Treatment consisted of anticoagulation (n = 39),
anticoagulation with CVC removal or replacement (n = 22),
other therapy (n = 7) or no therapy (n = 8). Regardless of
the intervention no patients had a major adverse outcome
such as pulmonary emboli, vascular comprise of a limb or
death. Only four patients did not have resolution of their
presenting symptoms, all of whom were treated with line
replacement [40].
Whether a CVC-related thrombosis necessitates the removal
of the CVC remains unclear. The decision of removal is usually
left to the discretion of the attending physician. Kovacs et al.
[41] recently assessed in a prospective cohort study the safety
and effectiveness of a management strategy for CVC-related
thrombosis in cancer patients consisting of dalteparin and
warfarin without the need for removal of the CVC. There
were no episodes of recurrent venous thrombo-embolism and
three (4%) major bleeds in 74 cancer patients. No lines were
removed due to infusion failure or recurrence/extension of
thrombosis.
Anticoagulation can preserve the life span of a CVC with
a CVC-related thrombosis. Lee et al. [17] did not find
436 | Boersma et al.
Annals of Oncology
a statistically significant difference in catheter life span between
cancer patients who did not have CVC-related thrombosis and
cases with a CVC-related thrombosis who were treated with
anticoagulation. However, their results should be interpreted
with caution because there were only 19 cases of CVC-related
thrombosis and they did not control for the use of
anticoagulation in their study.
The safety of LMWH in the treatment of CVC-related
thrombosis has been reported in the literature in five patients
undergoing bone marrow transplantation. No hemorrhagic
complications were seen in these five patients with protracted
thrombocytopenia [42].
No randomized comparison of thrombolytic therapy with
heparin has been performed in hematological or non-
hematological patients with a CVC-related thrombosis. In
a retrospective, non-randomized analysis of 95 patients with
a subclavian vein thrombosis systemic thrombolysis was
compared with anticoagulant therapy. Systemic thrombolysis
was associated with an acceptable primary technical success
rate, but a rather high frequency of bleeding complications
(21% versus none in the group of anticoagulants only) [43].
The conventional therapy for a blocked CVC resulting from
catheter tip occlusion or catheter sleeve occlusion is local
thrombolytic therapy with a low dose of single or repeated
bolus or urokinase, streptokinase or tissue plasminogen
activator. This therapy restores catheter patency in most
patients, providing the CVC is well positioned [44, 45].
There is no consensus regarding the treatment of
asymptomatic thrombosis. Since unrecognized thrombosis may
be clinically important [15] further prospective studies are
needed to determine whether the treatment of asymptomatic
thrombosis will prevent occlusion of the CVC or CVC-related
infection.
CVC-related infections
CVC-related infections can be divided into catheter
colonization, exit-site infection, tunnel infection and
bloodstream infection [46].
The prevalence of CVC-related bloodstream infections in
hematological patients varies from 0.0% to 20.8%, depending
on the patient and device characteristics and the definition
used for a CVC-related bloodstream infection (see Table 2).
Only a minority of these publications adhere to the US
Hospital Infection Control Practices Advisory Committee
(HICPAC) definitions for intravascular device-related
infections [47].
The risk of infection is particularly high in neutropenic
patients, patients undergoing myeloablative chemotherapy
followed by autologous stem cell transplantation or patients
with a CVC-related thrombosis [14, 48].
pathogenesis and etiology of CVC-related
infections
Following catheter insertion, a thrombin layer or sheath covers
the external and the internal surfaces of the intravascular
segment. This sheath, which is rich in host-derived proteins,
such as fibrin, fibronectin, thrombospondin and laminin,
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Annals of Oncology review
Table 2. Incidence of CVC-related bloodstream infections in hematological patients

Author Year Study design No. CVCs CVC-related

bacteremia, n (%)
Carratala et al. 1999 Prospective 57 heparin lock 4 (7.0)
60 heparin–vancomycin lock 0
Nouwen et al. 1999 Prospective 48 10 (20.8)
Lagro et al. 2000 Retrospective 390 46 (11.8)
Harter et al. 2002 Prospective 113 standard CVCs 10 (8.8)
120 silver-coated CVCs 6 (5)
Karthaus et al. 2002 Prospective 178 17 (9.6)
Cortelezzi et al. 2003 Retrospective 150, also PICCS 16 (10.6)
Lordick et al. 2003 Prospective 43 4 (9.3)
Nosari et al. 2004 Retrospective 227 23 (10.1)
Abdelkefi et al. 2005 Prospective 102 (heparin group) 7 (6.8)
102 (control group) 17 (16.6)
Cortelezzi et al. 2005 Prospective 458 21 (4.6)
Jaeger et al. 2005 Prospective 55 standard CVCs 8 (14.5)
55 CH-SS CVCs 1 (1.8)
Van Rooden et al. 2005 Prospective 105 14 (13.3)

PICCS: peripherally inserted central venous catheters.

CH-SS CVC: chlorhexidine and silver sulfadiazine impregnated central venous catheter.

promotes adherence of potential microbial pathogens to the
surface. Furthermore, staphylococci, Candida and some other
microbes produce a slimy material rich in exopolysaccharides,
resulting in the formation of a microbial biofilm. This biofilm
helps these organisms to adhere to and survive on the surfaces
of foreign bodies in the bloodstream [49].
The organisms causing a CVC-related infection can gain
access to the device through four different routes: invasion of
the skin insertion site, contamination of the catheter hub,
hematogenous spread from a distant site of infection or
infusion of contaminated fluid through the device [46, 50].
For tunneled CVCs, contamination of the catheter hub is
the most common route of infection. From the contaminated
hub, the organisms migrate along the internal surface of the
CVC, where they create a bloodstream infection. For short-
term, non-tunneled catheters, skin contamination is the
most likely route of infection, whereby organisms migrate
along the external surface of the CVC and the intercutaneous
and subcutaneous segments, leading to colonization of the
intravascular catheter tip, which may lead to bloodstream
infection [49, 50].
CVC-related infections in hematological patients are usually
caused by coagulase-negative Staphylococcus (62.5%),
Staphylococcus aureus (4.2%), Gram-negative bacilli such as
Enterobacteriaceae, Escherichia coli and Pseudomonas spp.
(29%) or Candida spp (4.2%) [8].
diagnosis of CVC-related infections
Diagnosis of CVC-related infections is notoriously difficult. In
daily care it may be difficult to discriminate between infection
and contamination. Clinical studies are hampered because of
the lack of a gold standard for the diagnosis. Clinical signs often
are unreliable at indicating the presence of a catheter-related
infection [51, 52]. Microbiological criteria are therefore
essential.
The most common techniques based on removal of the CVC
are Maki’s semi-quantitative culture and quantitative
endoluminal cultures. Quantitative cultures of the catheter
segment requires either flushing the segment with broth, or
vortexing, or sonicating it in broth, followed by serial dilutions
and surface plating on blood agar [53–55]. The most widely
used method is the semi-quantitative method, in which the
catheter segment is rolled across the surface of an agar plate and
colony-forming units are counted after overnight incubation
[56]. The major disadvantages of this roll plate method are that
only the external surface of the CVC is cultured and the need
for removal of the catheter. Since these catheters are often
integral to patient care in hematological patients, this often
requires re-insertion and exposing patients again to all risks
related to this procedure. The semi-quantitative roll plate
method is of limited usefulness in hematological patients
with mostly long-term catheters, in which the internal surface
is the predominant source of colonization and bloodstream
infection.
Diagnostic methods in which the CVC is left in situ include
paired quantitative blood cultures, paired qualitative blood
cultures with a continuously monitored differential time to
positivity or the endoluminal brush [46, 49, 57]. Quantitative
blood cultures drawn from the CVC and concomitantly by
venipuncture from a peripheral vein are time consuming and
expensive. If the CVC is infected the blood drawn through it
shows a 5-fold increase in the concentration of organisms
compared with the blood drawn percutaneously from
a peripheral vein. Safdar et al. [58] found in their meta-
analysis a sensitivity of 87% and a specificity of 98% and
concluded that paired quantitative blood cultures is the
most accurate diagnostic method in patients with long-term
CVCs.
The differential time to positivity (DTP) of paired CVC and
peripheral blood cultures provides comparable sensitivity and

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acceptable specificity (85% and 81%, respectively), at no
increased costs [58]. Abdelkefi et al. [59] showed that DTP is
useful for the diagnosis of catheter-related bloodstream
infection in hematopoietic stem cell transplant recipients (86%
sensitivity and 87% specificity).
Both culture techniques require a blood sample to be drawn
through the CVC lumen, but in 15–50% of cases this may not
be achieved [57, 60]. The endoluminal brush has no such
limitation and has a sensitivity of 100% and a specificity of 89%
[57]. It is theoretically possible to induce a peripheral
bacteremia by endoluminal brushing of colonized CVCs.
Dobbins et al. [61] found no peripheral bacteremia either 1 min
or 1 h post-brushing in any of eight cases with significant
endoluminal colonization. Few studies have assessed the
endoluminal brush and most of the studies identified were
performed by the same group of investigators. Since important
side-effects may theoretically occur, it is not a method that
can be recommended without further study.
prevention of CVC-related infections
Since the microbes that colonize the catheter hub and the skin
surrounding the insertion site are the source of most CVC-
related infections, prevention of CVC-related infections focuses
mainly on the essential measures of aseptic insertion technique
and proper catheter care.
Full barrier precautions during insertion of the CVC (sterile
gloves, long-sleeved sterile gown, mask, cap and large sterile
sheet drape) substantially reduces the incidence of CVC-related
bloodstream infections compared with standard precautions
(sterile gloves and small drape) (0.8/1000 and 0.5/1000
catheter-days, respectively; P = 0.02) [62].
Any attempt to reduce the routine number of CVC
manipulations at any site could reduce the risk of CVC-related
infections. Good training in catheter manipulations is probably
one of the best methods for guarding against CVC-related
bacteremias both in the hospital and at home. The presence
of a specialized team of nurses committed to the care of
CVCs or the knowledge of proper maintenance procedure
techniques shared by all nurses are both effective approaches
for the reduction of CVC-related infection incidence in
hospitalized patients [47, 63].
Continuing quality improvement programs to assure
compliance with catheter care guidelines significantly reduce
primary bloodstream infection [47, 63]. Moller et al. [64]
showed a reduction of >50% in the incidence rate of CVC-
related infections with a systematic, individualized, supervised
patient education program and self-care for the catheter.
To prevent CVC-related infections, antibiotic lock
prophylaxis has been attempted by flushing and filling the
lumen of the CVC with an antibiotic solution and leaving the
solution to dwell in the lumen of the CVC. In 126
immunocompromised children the use of either vancomycin/
ciprofloxacin/heparin (VCH) or vancomycin/heparin (VH)
compared with heparin alone significantly increased the time to
develop a CVC-related infection and decreased the amount
of Gram-positive CVC-related infections (VH, P = 0.028;
VHC, P = 0.022) [65]. However, the Centers for Disease Control
and Prevention guidelines recommend against prophylactic use
438 | Boersma et al.
Annals of Oncology
of vancomycin because it is an independent risk factor for
acquisition of vancomycin-resistant enterococci [66].
Systemic antibiotic prophylaxis at the time of CVC insertion
in 65 neutropenic patients has not been shown to reduce the
incidence of CVC-related bloodstream infection [67]. In
another study a single dose of teicoplanin did decrease the risk
of Gram-positive CVC-related infections in neutropenic
patients. The benefit of prophylactic teicoplanin was observed
particularly among patients who were already neutropenic at
the time of catheterization [68]. In the study of Ljungman [67]
only two patients were neutropenic at the time of CVC
insertion which is a possible explanation for the observed
difference.
Antiseptic-impregnated CVCs are effective in preventing
CVC-related infections. In a meta-analysis Veenstra et al. [69]
showed that short-term (<2 weeks) use of CVCs impregnated
with chlorhexidine/silver sulfadiazine reduced the risk of
CVC-related bloodstream infections by 40%. This meta-
analysis, however, was not limited to hematological patients.
Since most hematological patients have a CVC in situ for
more than 2 weeks, antiseptic impregnated CVCs did not prove
their interest in this patient population. In a prospective,
randomized trial in 106 patients with severe neutropenia, CVC-
related colonization and CVC-related bloodstream infections
were observed less frequently in the study group with
chlorhexidine and silver sulfadiazine impregnated CVCs
compared with the control group using a standard uncoated
CVC. The CVCs, however, were only in situ for a period of
2 weeks, which is a relatively short period of time for
hematological patients [70]. Logghe et al. [71] showed that the
use of antiseptic impregnated CVCs in hematological patients
reduced neither the overall risk of CVC-related bloodstream
infection, nor the CVC-related infection rate, nor the delay
for the occurrence of infections. The CVCs were in situ for
a mean of 20 days (SD 12 days). This finding probably
reflects reduced antimicrobial activity of the CVC over time
and a lack of protection from microbes invading the luminal
surface of the CVC from contaminated hubs [71].
Significant controversy surrounds the usefulness of CVCs
impregnated with antimicrobial agents for the prevention of
CVC-related bloodstream infections [72–74]. McConell et al.
[74] reviewed 11 trials of antimicrobial impregnated CVCs
versus uncoated CVCs and they concluded that there is a lack
of solid evidence to support a benefit of antimicrobial
impregnated CVCs in reducing the rate of CVC-related
bloodstream infections. Others assert that there is a large body
of evidence that demonstrates a powerful decrease in the risk of
infection [72, 73].
In a recently published meta-analysis Falagas et al. [75]
demonstrated that CVCs impregnated with rifampicin and
monocycline are safe and efficacious in reducing the rate of
catheter colonization and CVC-related bloodstream infections.
Most patients included in all reviews, however, were not
hematological patients.
Hanna et al. [76] performed a prospective study in hemato-
oncological patients with 356 CVCs who were randomized
between non-impregnated CVCs and CVCs impregnated with
minocycline/rifampin. Fourteen CVC-related bloodstream
infections occurred in the non-impregnated CVCs and only
Volume 19 | No. 3 | March 2008
Annals of Oncology
three occurred in the group with CVCs impregnated with
minocycline/rifampin (8% compared with 1.6%; P = 0.003).
The mean duration of catheterization was, respectively, 63.01 6
30.88 days and 66.21 6 30.88 days.
Since CVC-related thrombosis and infection are interrelated,
interventions designed to decrease fibrin deposition and
thrombus formation have the potential to reduce CVC-related
infections. Abdelkefi et al. [8] showed in a randomized study
that the use of a continuous infusion of heparin significantly
reduced the risk of CVC-related bloodstream infections.
treatment of CVC-related infections
Patients with a CVC-related infection should be separated
in those with complicated infections, into which there is
septic thrombosis, endocarditis, osteomyelitis or possible
metastatic seeding, and those with uncomplicated CVC-related
infections in which there is no evidence of such complications.
Patients with an uncomplicated CVC-related infection
should receive 10–14 days of antimicrobial therapy. Relapse,
continuous fever or bacteremia, despite removal of the catheter,
is consistent with the suspicion of a persistent focus of
infection. This implies prolonged (4–6 weeks) or modified
antimicrobial treatment and an active search for metastatic
abscess, septic thrombophlebitis or endocarditis.
If a patient has a removable CVC, the catheter should be
removed. Because removal of a tunneled (and thus surgically
implanted) CVC is often a management challenge, it is
important to be sure that one is dealing with a true CVC-
related bloodstream infection, rather than skin contamination,
catheter colonization or infections from another source. The
tunneled CVC may be left in situ in the presence of an
uncomplicated infection due to coagulase-negative
staphylococci. Removal is mandatory in severe or
complicated infections such as shock, persistent fever, persistent
bacteremia or bacteremia with certain microorganisms
(S. aureus, Gram-negative bacilli, Candida spp.) [46].
Raad et al. [77] showed recurrent bacteremia within 12 weeks
of standard parenteral therapy in 20% of patients whose
catheters were not removed, compared with only 3% of patients
whose catheters were removed. Explanation for this might be
the inability of most antibiotics to kill microorganisms in
a biofilm in therapeutically achievable concentrations.
Antibiotic lock therapy for CVC-related bloodstream infections
can be used in conjunction with systemic antibiotic therapy
and involves instilling a high concentration of an antibiotic
to which the causative microbe is susceptible in the catheter
lumen. The duration of antibiotic lock therapy is most often
2 weeks.
Randomized, prospective trials have demonstrated that
neutropenic patients with persistent fever despite broad-
spectrum antimicrobial therapy have a 20% risk of developing
an overt fungal infection. Empirical antifungal therapy
reduces the frequency of development of clinically overt
invasive fungal infection in this high-risk population [78].
In the case of non-neutropenic CVC-related candidemia, the
CVC should always be removed. Removal of the CVC is
controversial in neutropenic patients since a gastrointestinal
source is common. Duration of antifungal treatment for
Volume 19 | No. 3 | March 2008
review
candidemia should be at least 14 days after the last positive
blood culture result and resolution of signs and symptoms of
infections or resolved neutropenia [46, 79].
relationship between CVC-related
infections and thrombosis
There is accumulating evidence showing that CVC-related
thrombosis and infection are interrelated and can therefore not
be seen as separate entities. There seems to be a bi-directional
relationship [14, 29, 30].
A major contributing factor in both CVC-related thrombosis
and CVC-related infection might be fibrin sheath formation
around the external portion of the catheter and within the
catheter lumen [80].
The composition of CVC-related thrombi consists of several
proteins such as fibrin, fibronectin, collagen, laminin and
several types of immunoglobulins. Microorganisms, especially
S. aureus and Staphylococcus epidermidis, easily adhere to
thrombin sheaths [80, 81]. These microorganisms are able to
produce a coagulase enzyme that enhances the thrombogenic
process.
There is sufficient evidence that thrombosis affects
inflammation in more ways. Activated coagulation proteases
interact with protease-activated receptors which are believed to
play a role in translating coagulation products in inflammatory
signals. Thrombin induces upregulation of various
proinflammatory cytokines in vitro [82–84].
Lordick et al. [14] detected a CVC-related infection in 14 of
43 hemato-oncological patients. In 12 of the 14 patients with
a CVC-related infection a CVC-related thrombosis preceded
the CVC-related infection.
After an episode of CVC-related infection, the risk of
clinically manifest thrombosis is markedly increased. In a group
of patients with a CVC-related infection, the frequency of
subsequent clinically manifest thrombosis was 44% (11 of 25
patients), compared with 3% in patients without CVC-related
infection (2 of 80 patients). This yields a relative risk of 17.6.
The absolute risk of developing a clinically manifest thrombosis
increased with the severity of infection: a 57% thrombosis risk
was observed after an episode of CVC-related bloodstream
infection, compared with 27% in patients with a positive lock
fluid culture [29].
CVC-related infection might induce an inflammatory
response which can result in activation of coagulation, due to
tissue factor-mediated thrombin generation, downregulation of
physiological anticoagulant mechanisms and inhibition of
fibrinolysis. This could induce thrombus formation which
may further promote catheter colonization, bacterial biofilm
growth and eventually bloodstream seeding [83, 84].
Since CVC-related thrombosis and infection are interrelated,
interventions designed to decrease fibrin deposition and
thrombus formation have the potential to reduce CVC-related
infections. In a randomized study the use of a continuous
infusion of low-dose unfractionated heparin (100 U/kg per
day) to prevent CVC-related thrombosis and CVC-related
bloodstream infection in patients with hematological disease
was investigated. CVC-related bloodstream infection occurred
doi:10.1093/annonc/mdm350 | 439
review
in 6.8% (7 of 102 CVCs) of those in the heparin group and
in 16.6% (17 of 102 CVCs) of those in the control group
(P = 0.03). CVC-related thromboses were observed more
frequently in the control group (10 of 102) than in the
heparin group (2 of 102) (P = 0.017). Severe bleeding was
experienced by four patients in the heparin group and five
patients in the control group (P = 0.2) [8].
Urokinase administration every 2 weeks significantly affected
the rate of occlusive and infectious events in children with
a CVC compared with heparin administration [36].
In hemodialysis the use of trisodium citrate 30% was
compared with unfractionated heparin 5000 U/ml for catheter
locking. The risk reduction for CVC-related bacteremia was
87% for tunneled cuffed CVCs (P < 0.01) and 64% for
untunneled CVCs (P = 0.05) [85]. This effect warrants further
investigation in hematological patients.
conclusions
CVC-related thrombosis and infections are frequently
occurring complications and may cause significant morbidity
in patients with hematological malignancies. CVC-related
thrombosis and infection are related and can therefore not be
seen as separate entities.
There is need for a specific approach regarding diagnosis and
treatment of CVC-related thrombosis and infection with
specific attention to the preservation of the catheter.
It is clear that the prevention of CVC-related infections and
thrombosis is of utmost importance and will help to decrease
patient suffering as well as the costs of patient management.
Since the fibrin sleeve has been implicated as a major
contributing factor in both CVC-related thrombosis and CVC-
related infection, interventions designed to decrease fibrin
deposition seems to be the future.
Since data on CVC-related infections and thrombosis in
hematological patients have been obtained mainly from
retrospective studies of small sample size, prospective,
randomized studies of prophylactic measures concerning CVC-
related thrombosis and infection are warranted. Many topics
remain unsolved and there is still an urgent need for effective,
cheap and easy to implement preventive measures.
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